WO2007148073A1 - imagerie fonctionnelle de la rétine - Google Patents

imagerie fonctionnelle de la rétine Download PDF

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Publication number
WO2007148073A1
WO2007148073A1 PCT/GB2007/002282 GB2007002282W WO2007148073A1 WO 2007148073 A1 WO2007148073 A1 WO 2007148073A1 GB 2007002282 W GB2007002282 W GB 2007002282W WO 2007148073 A1 WO2007148073 A1 WO 2007148073A1
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WO
WIPO (PCT)
Prior art keywords
retina
sequences
images
optical
predetermined
Prior art date
Application number
PCT/GB2007/002282
Other languages
English (en)
Inventor
David Keating
Stuart Parks
Original Assignee
Greater Glasgow Health Board
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Greater Glasgow Health Board filed Critical Greater Glasgow Health Board
Priority to EP07733283A priority Critical patent/EP2028992A1/fr
Priority to US12/305,319 priority patent/US7980694B2/en
Publication of WO2007148073A1 publication Critical patent/WO2007148073A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/12—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes
    • A61B3/1225—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes using coherent radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/102—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for optical coherence tomography [OCT]

Definitions

  • Electrophysiology studies the electrical properties of tissues and cells by measurement of changes in potential differences or of the flow of electrical currents therein.
  • ERGs electroretinograms
  • An ERG is a measurement of the electrical response of the retina to a full field sensory stimulus and is a triphasic waveform which carries information about the behaviour of various cell types in the retina. It is a composite global response generated by different cellular mechanisms, for example, those of the light sensitive rods and cones and the ganglion cells.
  • An ERG is obtained by placing electrodes on the cornea and on the skin adjacent to the eye, and measuring the electrical signal which is produced in response to a stimulus as a function of time. ERGs may be used in the diagnosis of retinal diseases such as retinitis pigmentosa and congenital stationary night blindness.
  • This method has a number of drawbacks. Firstly, it is generally uncomfortable to place electrodes on the cornea of a patient. Furthermore, because physical contact with the eye is necessary, the procedure must be carried out in a hospital environment and is therefore not a service suitable for general optical practitioners, such as high street opticians, to provide. Also, as the method uses a non-localised stimulus, the response measured is a bulk response of the retina as a whole from which it would be difficult to obtain accurate information about specific locations on the retina.
  • Multifocal ERG uses a number of distinct stimulus sequences to stimulate different regions of the retina simultaneously. As each sequence is distinct, the response for each region may be determined by cross- correlation of the known distinct stimulus sequences with a measurement from a single corneal electrode.
  • US Patent No. 4,846,567 describes a multifocal ERG technique in which identical, time-shifted, maximum length sequences (m-sequences) are used to visually stimulate the retina. Electrical signals are measured by means of an electrode placed on the eye, and the measured electrical signals correlated with the m-sequences to determine an electrical response for each m-sequence.
  • m-sequences identical, time-shifted, maximum length sequences
  • an apparatus for obtaining images of a retina comprising: one or more light sources adapted to provide one or more optical stimuli to the retina in accordance with one or more predetermined stimulation sequences; one or more imaging means adapted to obtain one or more images of the retina; and one or more processing means adapted to correlate the one or more images of the retina with the one or more predetermined stimulation sequences so as to determine one or more responses of the retina to each of the one or more optical stimuli.
  • the apparatus may therefore determine one or more responses using an imaging means which has the benefit of being non-invasive and non-contact. Furthermore, correlating the obtained images with the one or more predetermined stimulation sequences enables the apparatus to determine the individual responses of the retina caused by each of the optical stimuli .
  • the one or more light sources may include broadband light sources such as ultrabright LEDs, femtosecond lasers or white light sources, or single frequency light sources such as narrowband LEDs, semiconductor lasers or white light sources with appropriate filters applied.
  • Image sources such as cathode ray tubes (CRT) or liquid crystal display (LCD) devices may also be employed.
  • the one or more light sources are adapted to simultaneously provide one or more optical stimuli to the retina in accordance with the one or more predetermined stimulation sequences.
  • a number of responses may be determined in one measurement, thereby reducing the amount of time required to determine multiple responses.
  • the one or more light sources are adapted to provide an optical stimulus to separate locations on the retina.
  • a number of responses may be determined in one measurement which correspond to a number of different locations on the retina, rather than a bulk measurement where pinpointing particular areas is difficult.
  • the one or more light sources comprises a two-dimensional array of a plurality of light sources. 1 This means that the one or more light sources may be
  • the one or more light sources comprises an
  • OLED organic light emitting diode
  • an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source. It is envisaged that an OLED display may be any organic light source.
  • the one or more predetermined stimulus is selected from the one or more predetermined stimulus.
  • sequences comprise one or more pseudo-random binary
  • the pseudo-random binary sequences preferably comprise
  • the one or more predetermined stimulus 31 sequences comprise one or more m-sequences.
  • 32 M-sequences are useful for determining impulse responses, impart more energy to the retina because they are longer than standard sequences, and also result in a higher signal to noise ratio. They are also spectrally flat.
  • the one or more predetermined stimulus sequences comprise a plurality of m-sequences overlapping by a predetermined temporal overlap.
  • the one or more predetermined stimulus sequences comprise a plurality of m-sequences staggered by a predetermined temporal spacing.
  • the one or more predetermined stimulus sequences comprise a plurality of substantially identical m-sequences overlapping by a predetermined temporal overlap.
  • the one or more predetermined stimulus sequences comprise a plurality of substantially identical m-sequences staggered by a predetermined temporal spacing.
  • m-sequence Another benefit of the m-sequence is that by their nature multiple identical or near-identical m-sequences can be used, substantially overlapping or spaced in time, and each still remain detectable.
  • the apparatus further comprises one or more sequence generators adapted to generate the one or more predetermined stimulation sequences.
  • sequence generators adapted to generate the one or more predetermined stimulation sequences.
  • particular sequences can be generated depending on the application.
  • suitable m- sequences can be generated dependent on criteria such as maximum measurement time, desired signal to noise etc.
  • At least one of the one or more imaging means is adapted to obtain one or more optical coherence tomography images of the retina.
  • OCT optical coherence tomography
  • At least one of the one or more imaging means is adapted to obtain one or more reflectance images of the retina.
  • Obtaining reflectance images of the retina provides a visual map of the surface of the retina which may also be compared with or correlated with the stimulation sequences. These images may be obtained by scanning laser ophthalmoscopy (SLO) or standard digital colour cameras.
  • SLO scanning laser ophthalmoscopy
  • the one or more processing means determines the response of the retina to the predetermined stimulation sequences by determining an electrical signal as a function of time.
  • the apparatus may provide a temporal correlation between the retinal response corresponding to the signal and the stimulation which is known as a function of time.
  • the processing means determines an optical change between at least two of the one or more images.
  • An optical change in a region of the retina may be the result of underlying physical processes which effect a change in the reflectance properties of retinal cells in that region. This provides a measurement of the functional integrity of the retinal cells.
  • the apparatus further comprises one or more synchronisation means adapted to synchronise the one or more imaging means with the one or more predetermined stimulus sequences.
  • each image can be cross-correlated with a particular stimulus sequence event .
  • a method for obtaining images of a retina comprising the steps of: (a) providing one or more optical stimuli to the retina in accordance with one or more predetermined stimulation sequences; (b) obtaining one or more images of the retina; and (c) correlating the one or more images of the retina with the one or more predetermined stimulation sequences; and (d) determining one or more responses of the retina to each of the one or more optical stimuli.
  • the method determines one or more responses using an imaging means which has the benefit of being non-invasive and non-contact. Furthermore, correlating the obtained images with the one or more predetermined stimulation sequences determines the individual responses of the retina due to each of the optical stimuli.
  • the optical stimuli may be provided by broadband light sources such as ultrabright LEDs, femtosecond lasers or white light sources, or single frequency light sources such as narrowband LEDs, semiconductor lasers or white light sources with appropriate filters applied.
  • Image sources such as cathode ray tubes (CRT) or liquid crystal display (LCD) devices may also be employed.
  • the one or more optical stimuli are provided simultaneously to the retina in accordance with the one or more predetermined stimulation sequences.
  • a number of responses can thus be determined in one measurement, reducing the amount of time required to determine multiple responses.
  • the step of providing one or more optical stimuli comprises providing one or more optical stimuli to separate locations on the retina.
  • a number of responses can be determined in one measurement which corresponds to a number of different locations on the retina.
  • the step of providing one or more optical stimuli comprises providing one or more optical stimuli to the retina in accordance with one or more m-sequences .
  • M-sequences are useful for determining impulse responses, impart more energy to the retina because they are longer than standard sequences, and result in a higher signal to noise ratio.
  • the step of providing one or more optical stimuli comprises separating each of the one or more m- sequences by a predetermined temporal spacing.
  • m-sequence Another benefit of the m-sequence is that by their nature multiple identical m-sequences can be used, spaced in time, and each still remain detectable.
  • the method further comprises the step of generating the one or more predetermined stimulation sequences.
  • the step of obtaining one or more images comprises obtaining one or more optical coherence tomography images of the retina.
  • OCT optical coherence tomography
  • the step of obtaining one or more images comprises obtaining one or more reflectance images of the retina.
  • Obtaining reflectance images of the retina provides a visual map of the surface of the retina which may also be compared with or correlated with the stimulation sequences . These images may be obtained by scanning laser ophthalmoscopy (SLO) or standard digital colour cameras .
  • SLO scanning laser ophthalmoscopy
  • the step of determining the response of the retina to each of the one or more optical stimuli comprises determining an electrical signal as a function of time.
  • the apparatus may provide a temporal correlation between the retinal response corresponding to the signal and the stimulation which is known as a function of time.
  • the step of determining the response of the retina to each of the one or more optical stimuli comprises determining an optical change between at least two of the one or more images.
  • An optical change in a region of the retina may be the result of underlying physical processes which effect a change in the reflectance properties of retinal cells in that region. This provides a measurement of the functional integrity of the retinal cells.
  • the method further comprises the step of synchronising the one or more imaging means with the one or more predetermined stimulus sequences.
  • each image can be cross-correlated with a particular stimulus sequence event .
  • a module for processing images of ' a retina comprising: image input means adapted to receive one or more images of the retina; sequence input means adapted to receive one or more sequences corresponding with the one or more images of the retina; and one or more processing means adapted to correlate the one or more images of the retina with the one or more sequences so as to determine one or more responses of the retina to each of the one or more optical stimuli.
  • the module may be incorporated into existing systems so as to allow them to take advantage of the present invention.
  • the processing means determines an optical change between at least two of the one or more images.
  • the processing means determines an optical change between at least two of the one or more images as a function of time.
  • An optical change in a region of the retina may be the result of underlying physical processes which effect a change in the reflectance properties of retinal cells in that region. This provides a measurement of the functional integrity of the retinal cells. Additionally, determining this change as a function of time provides temporal information which can be correlated with the one or more sequences .
  • At least one computer program comprising program instructions, which, when loaded into at least one computer, constitutes the one or more processing means of the first aspect.
  • At least one computer program comprising program instructions, which, when loaded into at least one computer, constitutes the one or more processing means of the third aspect.
  • At least one computer program comprising program instructions, which, when loaded into at least one computer, cause the at least one computer to perform the method of according to the second aspect.
  • the computer programs are embodied on a recording medium or read-only memory, stored in at least one computer memory, or carried on an electrical carrier signal.
  • Figure 1 illustrates in schematic form the acquisition of images of the retina in accordance with an aspect of the present invention
  • Figure 2 illustrates a typical stimulation pattern projected onto a retina
  • Figure 3 illustrates a typical optical coherence tomography image of a retina corresponding with that illustrated in Figure 2.
  • the apparatus 1 comprises an m-sequence generator 2 which generates maximum length sequences in accordance with predetermined constraints such as required length, desired signal to noise ratio or maximum measurement time.
  • the generated m-sequence is transferred to a control system 3 which converts the binary m-sequence into an output which drives the optical output array 4.
  • the optical output array 4 comprises a large number of light sources which are each driven by separate, identical but temporally staggered, m-sequences.
  • the output array is an OLED display adapted to illuminate the retina in nineteen distinct groupings (see for example Figure 2 below) .
  • An optical coherence tomography (OCT) device 5 obtains OCT images (see for example Figure 3 below) in synchrony with the m-sequences such that each image can be correlated with a specific m-sequence event by the processing means 6. For example, for a known m-sequence, all OCT images where the corresponding optical stimulus was active can be identified and a mean calculated for that particular optical stimulus. As the particular optical stimulus is directed to a particular region of the retina (as in Figure 2 below) , functional information about those regions of the retina can therefore be determined.
  • the processing means 6 carries out the abovementioned image processing, but also controls the apparatus 1, synchronises the optical stimulation and the image acquisition, as well as providing a visual display 7 for an operator.
  • the m-sequence generator 2 may be dispensed with in the eventuality that the maximum length sequences are in fact preset and simply extracted from memory (preferably non-volatile) in the control system 3.
  • Figure 2 illustrates the illumination of a retina by the optical output array 4 of Figure 1.
  • the OLED display effects nineteen distinct areas of illumination, in this example each area is roughly hexagonal.
  • the m-sequences corresponding with each area cause the control system 3 to switch the illumination between an "on” condition (for example, see reference numeral 8) and an "off” condition (for example, see reference numeral 9) in that area.
  • FIG. 3 illustrates a typical OCT image 10 acquired along line A of Figure 2.
  • the OCT image 10. is a cross sectional view of the retina and reveals, in high resolution, the structure of the retina. This structure reveals, at a cellular level, the physical reaction of the retina to the optical stimulation.
  • the present invention allows measurement of the optical response, and hence determination of functional response, at a cellular level. This is achieved by a combination of improved precision and measurement at the cellular level of high resolution cross sectional images.
  • m-sequences results in an improved signal to noise ratio, while maintaining the facility for multiple sequences to be employed (albeit with a time delay between each) .
  • the mean of all the images obtained when the stimulus is inactive is subtracted from the mean of all the images obtained when the stimulus is active.
  • different frequencies and different intensities of optical stimulation may be used in order to stimulate different cellular structures. For example, red, green and blue stimuli may be employed to test the response of the corresponding cones .
  • optical responses can be determined at the cellular level with, for example, OCT images, it may be possible to diagnose conditions which are difficult to recognise with current technology.
  • Changes in the reflectance of the photoreceptor layer may be indicative of diseases such as retinitis pigmentosa or cone dystrophy, and changes in the reflectance of the ganglion cell layer may be symptomatic of glaucoma.
  • the apparatus and method of the present invention will allow a general optical practitioner such as an optician to be able to determine the response of a patient's retina to optical stimuli without the discomfort or additional medical supervision required with conventional systems. Furthermore, the structure of the eye can be monitored and correlated with the stimulation.
  • Medical trials for example on new drugs, may be monitored in the eye as systemic toxicity is evident in the eye. Furthermore, during medical trials side-effects may manifest themselves early on in the eye and monitoring the eye over time using the present invention will allow progress of the side-effects to be recorded.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Eye Examination Apparatus (AREA)

Abstract

L'invention concerne un appareil et un procédé pour obtenir, in vivo, une mesure de la réponse rétinienne à un stimulus optique. Des sources lumineuses produisent des stimuli optiques sur la rétine selon des séquences de stimulation prédéterminées, et des images de la rétine sont obtenues et corrélées avec les séquences de stimulation prédéterminées de façon à déterminer les réponses de la rétine aux stimuli optiques. Dans un mode de réalisation particulier, des stimuli optiques sont produits selon des séquences m et corrélées à des images de tomographie de cohérence optique correspondantes pour déterminer une réponse fonctionnelle de la rétine.
PCT/GB2007/002282 2006-06-19 2007-06-19 imagerie fonctionnelle de la rétine WO2007148073A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07733283A EP2028992A1 (fr) 2006-06-19 2007-06-19 Imagerie fonctionelle de la retine
US12/305,319 US7980694B2 (en) 2006-06-19 2007-06-19 Functional imaging of the retina

Applications Claiming Priority (2)

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GBGB0612096.8A GB0612096D0 (en) 2006-06-19 2006-06-19 Functional imaging of the retina
GB0612096.8 2006-06-19

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Cited By (6)

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WO2009089509A1 (fr) * 2008-01-09 2009-07-16 The Uab Research Foundation Procédé de détection d'une modification physiologique d'un neurone d'une rétine
US9757039B2 (en) 2008-07-10 2017-09-12 Ecole Polytechnique Federale De Lausanne (Epfl) Functional optical coherent imaging
US10101571B2 (en) 2012-07-10 2018-10-16 Novadaq Technologies ULC Perfusion assessment multi-modality optical medical device
US10169862B2 (en) 2015-05-07 2019-01-01 Novadaq Technologies ULC Methods and systems for laser speckle imaging of tissue using a color image sensor
US10575737B2 (en) 2012-04-27 2020-03-03 Novadaq Technologies ULC Optical coherent imaging medical device
EP3769665A1 (fr) * 2019-07-26 2021-01-27 Optos PLC Traitement fonctionnel de données de tomographie par cohérence optique

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WO2011034947A2 (fr) 2009-09-15 2011-03-24 University Of Washington Réactifs et procédés pour moduler l'activité des photorécepteurs à cônes
TWI698240B (zh) 2012-05-15 2020-07-11 澳大利亞商艾佛蘭屈澳洲私營有限公司 使用腺相關病毒(aav)sflt-1治療老年性黃斑部退化(amd)
CA2942776C (fr) 2014-03-17 2023-01-24 Adverum Biotechnologies, Inc. Cassettes polynucleotidiques et vecteurs d'expression pour l'expression d'un gene dans des cones retiniens a l'aide d'un promoteur de m-opsine tronque
EA201791939A1 (ru) 2015-03-02 2018-01-31 Адверум Байотекнолоджиз, Инк. Композиции и способы интравитреальной доставки полинуклеотидов в колбочки сетчатки
WO2016154066A2 (fr) 2015-03-20 2016-09-29 Glaukos Corporation Dispositifs gonioscopiques
GB2545763A (en) 2015-12-23 2017-06-28 Adverum Biotechnologies Inc Mutant viral capsid libraries and related systems and methods
AU2017382218B2 (en) 2016-12-21 2023-05-11 Acucela Inc. Miniaturized mobile, low cost optical coherence tomography system for home based ophthalmic applications
US10674906B2 (en) 2017-02-24 2020-06-09 Glaukos Corporation Gonioscopes
USD833008S1 (en) 2017-02-27 2018-11-06 Glaukos Corporation Gonioscope
WO2019246412A1 (fr) 2018-06-20 2019-12-26 Acucela Inc. Système de tomographie par cohérence optique à faible coût et mobile miniaturisé pour applications ophtalmiques à domicile
US11730363B2 (en) 2019-12-26 2023-08-22 Acucela Inc. Optical coherence tomography patient alignment system for home based ophthalmic applications
US10959613B1 (en) 2020-08-04 2021-03-30 Acucela Inc. Scan pattern and signal processing for optical coherence tomography
WO2022035809A1 (fr) 2020-08-14 2022-02-17 Acucela Inc. Système et procédé d'alignement par courbure décroissante de balayage a de tomographie par cohérence optique
US11393094B2 (en) 2020-09-11 2022-07-19 Acucela Inc. Artificial intelligence for evaluation of optical coherence tomography images
CN116322471A (zh) 2020-09-30 2023-06-23 奥克塞拉有限公司 近视预测、诊断、计划和监测设备
US11497396B2 (en) 2021-03-24 2022-11-15 Acucela Inc. Axial length measurement monitor

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089509A1 (fr) * 2008-01-09 2009-07-16 The Uab Research Foundation Procédé de détection d'une modification physiologique d'un neurone d'une rétine
US9757039B2 (en) 2008-07-10 2017-09-12 Ecole Polytechnique Federale De Lausanne (Epfl) Functional optical coherent imaging
EP2309919B1 (fr) * 2008-07-10 2019-03-06 Ecole Polytechnique Federale De Lausanne (EPFL) EPFL-TTO Imagerie optique cohérente fonctionnelle
US10617303B2 (en) 2008-07-10 2020-04-14 Ecole Polytechnique Federale De Lausanne (Epfl) Functional optical coherent imaging
US10575737B2 (en) 2012-04-27 2020-03-03 Novadaq Technologies ULC Optical coherent imaging medical device
US10101571B2 (en) 2012-07-10 2018-10-16 Novadaq Technologies ULC Perfusion assessment multi-modality optical medical device
US10169862B2 (en) 2015-05-07 2019-01-01 Novadaq Technologies ULC Methods and systems for laser speckle imaging of tissue using a color image sensor
EP3769665A1 (fr) * 2019-07-26 2021-01-27 Optos PLC Traitement fonctionnel de données de tomographie par cohérence optique
NL2023578B1 (en) * 2019-07-26 2021-02-18 Optos Plc Functional OCT Data Processing
US11540712B2 (en) 2019-07-26 2023-01-03 Optos Plc Functional OCT data processing
US11857257B2 (en) 2019-07-26 2024-01-02 Optos Plc Functional oct data processing

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US7980694B2 (en) 2011-07-19
US20090128776A1 (en) 2009-05-21
GB0612096D0 (en) 2006-07-26
EP2028992A1 (fr) 2009-03-04

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